Rapamycin Improves the Response of Effector and Memory CD8(+) T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Author(s):Show less -

Moraschi, Barbara Ferri ^{[1, 2]} ; Noronha, Isau Henrique ^{[1, 2]} ; Ferreira, Camila Pontes ^{[1, 2]} ; Cariste, Leonardo M. ^[3] ; Monteiro, Caroline B. ^[3] ; Denapoli, Priscila ^[2] ; Vrechi, Talita ^[4] ; Pereira, Gustavo J. S. ^[4] ; Gazzinelli, Ricardo T. ^{[5, 6]} ; Lannes-Vieira, Joseli ^[7] ; Rodrigues, Mauricio M. ^{[1, 2]} ; Bortoluci, Karina R. ^{[4, 2]} ; Vasconcelos, Jose Ronnie C. ^{[1, 2, 3]}

Affiliation

^[1] Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Sao Paulo - Brazil

^[2] Fed Univ Sao Paulo UNIFESP, Ctr Mol & Cellular Therapy, Mol Immunol Lab, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Recombinant Vaccines Lab, Dept Biosci, Santos, SP - Brazil

^[4] Fed Univ Sao Paulo UNIFESP, Dept Pharmacol, Sao Paulo - Brazil

^[5] Fiocruz MS, Rene Rachou Res Ctr, Belo Horizonte, MG - Brazil

^[6] Univ Massachusetts, Med Sch, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01605 - USA

^[7] Fiocruz MS, Oswaldo Cruz Inst, Laboratoy Biol Interact, Rio De Janeiro - Brazil

• Document type: Journal article
• Source: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY; v. 11, MAY 25 2021.
• Web of Science Citations: 1

Abstract

Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8(+) T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8(+) T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8(+) T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8(+) T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8(+) T-cells and the percentage of the polyfunctional population, which degranulated (CD107a(+)) and secreted both interferon gamma (IFN gamma) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8(+) T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8(+) T-cell response. (AU)

• FAPESP's process: 18/15607-1 - Role of specific CD4+ and CD8+ T cells generated by different vaccination protocols against experimental Trypanosoma cruzi infection
• Grantee: Jose Ronnie Carvalho de Vasconcelos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 16/02840-4 - Role of pharmacological inhibitor mTOR rapamycin in response of memory CD8+ T cells induced by heterologous prime-boost immunization
• Grantee: Barbara Ferri Moraschi
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/08814-2 - Role of integrin receptors and chemokines in the migration of specific CD8+ T cells generated by genetic immunization with ASP -2 Trypanosoma cruzi
• Grantee: Camila Pontes Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/19422-5 - Pharmacological effect of the mTOR inhibitor rapamycin in response to memory CD8+ t lymphocytes induced by genetic immunization using heterologous prime-boost
• Grantee: Barbara Ferri Moraschi
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 12/22514-3 - Migration study of specific T cells generated by vaccination or Trypanosoma cruzi infection
• Grantee: Jose Ronnie Carvalho de Vasconcelos
• Support Opportunities: Research Grants - Young Investigators Grants